Circulating concentrations of the hepatic enzymes gamma glutamyl transferase (GGT), alanine amino transferase (ALT), alkaline phosphatase (ALP) and complement fraction 3 (C3) are elevated in several human diseases including e.g., nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), metabolic syndrome (MS), type 2 diabetes (T2DM), cardiovascular disease (CVD), chronic kidney disease and cancer (see e.g., Ghouri N, et al. (2010) Hepatology, 52:1156-61; Oh R. C., Hustead T. R. (2011) American family physician 84:1003-8; Targher G. (2010) Clinical chemistry and laboratory medicine: CCLM/FESCC 48:147-57). Circulating concentrations of the hepatic enzymes are also increased in alpha antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, thyroid disorders, celiac disease, hemolysis, and muscle disorders. These diseases are a major burden on the health systems worldwide and cost hundreds of billions of dollars yearly in management and loss of work.
Reference ranges for circulating hepatic enzymes vary with the gender, race, and the instrument used (see e.g., Dutta A., et al. (2009) Hepatology 50:1957-62; Neuschwander-Tetri B A, et al. (2008) Archives of internal medicine 168:663-6). In fact, the upper limit of normal for ALT in USA varies two fold, possibly due to the use of markedly different or undefined reference population (see e.g., Ruhl C. E. and Everhart J. E. (2012) Hepatology 55:447-54). However, even within the so called normal ranges, elevations in liver GGT, ALT, and ALP are associated with chronic inflammatory diseases such as e.g., atherosclerosis, stroke, and CVD (see e.g., Mistry D., Stockley R. A. (2010) Journal of Chronic Obstructive Pulmonary Disease 7:285-90; Ghouri N. et al (2010) supra; Pompella A, et al. (2004) Clinical chemistry and laboratory medicine: CCLM/FESCC. 42:1085-91.) Indeed, mortality from T2DM, liver disease, CVD, cancer, and all causes increases 2-4 fold when individuals in the highest and lowest quartiles for GGT and ALT are compared (see e.g., Kazemi-Shirazi L., et al. (2007) Clinical chemistry 53:940-6; Targher G. (2010) supra; Ruhl C. E. and Everhart J. E. (2009) Gastroenterology. 136:477-85).
Furthermore, increased levels of GGT are associated with increased mortality in lung transplantation for cystic fibrosis (see e.g., Wree A., et al. (2012) Transplant international: official journal of the European Society for Organ Transplantation 25:78-86) and increased overall cancer risk (see e.g., Corti A., et al. (2010) Anticancer research. 30:1169-81; Pompella A. et al. (2007) Current opinion in pharmacology 7:360-6; Targher G. (2010) supra, Fentiman I. S. (2012) British journal of cancer 106:1467-8; Van Hemelrijck M., et al., (2011) Eur J Cancer 47:2033-41; Strasak A. M., et al. (2008) Cancer research 68:3970-7; Strasak A. M., et al. (2008) International journal of cancer Journal international du cancer 123:1902-6). Elevated levels of GGT are also associated with an increase the incidence of tissue specific types of cancers, including e.g., cervical (see e.g., Seebacher V., et al., (2012) British journal of cancer 106:1551-5; Polterauer S., et al., (2011) Gynecologic oncology 122:590-4; Strasak A. M., et al. (2010), Cancer research 70:3586-93), liver (see e.g., Zhang J. B., et al., (2011) European journal of gastroenterology & hepatology 23:787-93), prostate (see e.g., Van Hemelrijck M., et al., (2011) supra), Lungs (Wree A. et al. (2012) supra, Bechmann L. P., et al. (2012) Transplant international: official journal of the European Society for Organ Transplantation. 2012; 25:78-86.), digestive organs, lymphoid and hematopoietic cancers (see e.g., Targher G. (2010) supra; Corti A. et al. (2010) Anticancer research 30:1169-81).
Given the association of increased levels of liver enzyme with chronic disease, it is clear that a need exists for methods and compositions effective for reducing levels of liver enzymes. As will be clear from the following disclosure, the present invention provides for this and other needs.